Milla Rosengård-Bärlund

The Presence and Severity of Chronic Kidney Disease Predicts All-Cause Mortality in Type 1 Diabetes

OBJECTIVES This study aimed to identify clinical features associated with premature mortality in a large contemporary cohort of adults with type 1 diabetes. RESEARCH DESIGN AND METHODS The Finnish Diabetic Nephropathy (FinnDiane) study is a national multicenter prospective follow-up study of 4,201 adults with type 1 diabetes from 21 university and central hospitals, 33 district hospitals, and 26 primary health care centers across Finland. RESULTS During a median 7 years of follow-up, there were 291 deaths (7%), 3.6-fold (95% CI 3.2–4.0) more than that observed in the age- and sex-matched general population. Excess mortality was only observed in individuals with chronic kidney disease. Individuals with normoalbuminuria showed no excess mortality beyond the general population (standardized mortality ratio [SMR] 0.8, 95% CI 0.5–1.1), independent of the duration of diabetes. The presence of microalbuminuria, macroalbuminuria, and end-stage kidney disease was associated with 2.8, 9.2, and 18.3 times higher SMR, respectively. The increase in mortality across each stage of albuminuria was equivalent to the risk conferred by preexisting macrovascular disease. In addition, the glomerular filtration rate was independently associated with mortality, such that individuals with impaired kidney function, as well as those demonstrating hyperfiltration, had an increased risk of death. CONCLUSIONS An independent graded association was observed between the presence and severity of kidney disease and mortality in a large contemporary cohort of individuals with type 1 diabetes. These findings highlight the clinical and public health importance of chronic kidney disease and its prevention in the management of type 1 diabetes.

New susceptibility loci associated with kidney disease in Type 1 diabetes

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Metabolic Phenotypes, Vascular Complications and Premature Deaths in a Population of 4,197 Patients with Type 1 Diabetes

OBJECTIVE—Poor glycemic control, elevated triglycerides, and albuminuria are associated with vascular complications in diabetes. However, few studies have investigated combined associations between metabolic markers, diabetic kidney disease, retinopathy, hypertension, obesity, and mortality. Here, the goal was to reveal previously undetected association patterns between clinical diagnoses and biochemistry in the FinnDiane dataset. RESEARCH DESIGN AND METHODS—At baseline, clinical records, serum, and 24-h urine samples of 2,173 men and 2,024 women with type 1 diabetes were collected. The data were analyzed by the self-organizing map, which is an unsupervised pattern recognition algorithm that produces a two-dimensional layout of the patients based on their multivariate biochemical profiles. At follow-up, the results were compared against all-cause mortality during 6.5 years (295 deaths). RESULTS—The highest mortality was associated with advanced kidney disease. Other risk factors included 1) a profile of insulin resistance, abdominal obesity, high cholesterol, triglycerides, and low HDL2 cholesterol, and 2) high adiponectin and high LDL cholesterol for older patients. The highest population-adjusted risk of death was 10.1-fold (95% CI 7.3–13.1) for men and 10.7-fold (7.9–13.7) for women. Nonsignificant risk was observed for a profile with good glycemic control and high HDL2 cholesterol and for a low cholesterol profile with a short diabetes duration. CONCLUSIONS—The self-organizing map analysis enabled detailed risk estimates, described the associations between known risk factors and complications, and uncovered statistical patterns difficult to detect by classical methods. The results also suggest that diabetes per se, without an adverse metabolic phenotype, does not contribute to increased mortality.

Physical Activity and Diabetes Complications in Patients With Type 1 Diabetes: The Finnish Diabetic Nephropathy (FinnDiane) Study

Physical activity exerts numerous beneficial health effects, and the evidence favoring a physically active lifestyle in the treatment of chronic diseases is substantial (1). For patients with diabetes, physical activity is considered important (2). In theory, regular physical activity may prevent diabetes complications through beneficial effects on glycemic control, insulin sensitivity, blood pressure, lipid profile, and endothelial function. However, physical activity could also cause adverse effects or patients may not be able to exercise due to complications. Little, however, is known about the relationship between physical activity and diabetes complications (3). Therefore, we investigated the associations between physical activity and microvascular and macrovascular diabetic complications in a large cohort of patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study. The FinnDiane Study and the assessment of self-reported leisure-time physical activity (LTPA) by a questionnaire have previously been described (4). This is a cross-sectional analysis of 1,945 patients with data on LTPA. Renal status was based on at least three urine collections. Renal function was evaluated by the Cockcroft-Gault formula (5) for estimated creatinine clearance. Data on retinopathy and cardiovascular disease (CVD) were obtained from medical records. Differences between groups were …

Lipid abnormalities predict progression of renal disease in patients with type 1 diabetes

Aims/hypothesisWe studied the impact of baseline lipid variables on the progression of renal disease in a large nationwide prospective cohort of patients with type 1 diabetes.MethodsA total of 2,304 adult patients with type 1 diabetes and available lipid profiles participating in the Finnish Diabetic Nephropathy Study (FinnDiane) were evaluated. Data on progression of renal disease were verified from medical files and patients were followed for 5.4 ± 2.0 (mean ± SD) years.ResultsHigh triacylglycerol, apolipoprotein (Apo) B, ApoA-II and HDL3-cholesterol concentrations predicted incident microalbuminuria. Progression to macroalbuminuria was predicted by high triacylglycerol and ApoB. When AER was entered into the model, triacylglycerol was no longer an independent predictor, but when patients with normal AER and microalbuminuria at baseline were pooled, triacylglycerol, HbA1c, male sex and AER were all independent predictors of renal disease. High total cholesterol, LDL-cholesterol, non-HDL-cholesterol and triacylglycerol as well as low HDL-cholesterol, HDL2-cholesterol, ApoA-I and ApoA-II concentrations were predictive of progression to end-stage renal disease. However, when estimated GFR was entered into the model, only total cholesterol remained an independent predictor of progression.Conclusions/interpretationLipid abnormalities, particularly high triacylglycerol concentrations, increase the risk of progression of renal disease.

Early autonomic dysfunction in type 1 diabetes: a reversible disorder?

Aims/hypothesisCardiac autonomic neuropathy is associated with increased morbidity and mortality rates in patients with type 1 diabetes. The prevalence of early autonomic abnormalities is relatively high compared with the frequency of manifest clinical abnormalities. Thus, early autonomic dysfunction could to some extent be functional and might lead to an organic disease in a subgroup of patients only. If this is true, manoeuvres such as slow deep-breathing, which can improve baroreflex sensitivity (BRS) in normal but not in denervated hearts, could also modify autonomic modulation in patients with type 1 diabetes, despite autonomic dysfunction.MethodsWe compared 116 type 1 diabetic patients with 36 matched healthy control participants and 12 heart-transplanted participants with surgically denervated hearts. Autonomic function tests and spectral analysis of heart rate and blood pressure variability were performed. BRS was estimated by four methods during controlled (15 breaths per minute) and slow deep-breathing (six breaths per minute), and in supine and standing positions.ResultsConventional autonomic function tests were normal, but resting spectral variables and BRS were reduced during normal controlled breathing in patients with type 1 diabetes. However, slow deep-breathing improved BRS in patients with type 1 diabetes, but not in patients with surgically denervated hearts. Standing induced similar reductions in BRS in diabetic and control participants.Conclusions/interpretationAlthough we found signs of increased sympathetic activity in patients with type 1 diabetes, we also observed a near normalisation of BRS with a simple functional test, indicating that early autonomic derangements are to a large extent functional and potentially correctable by appropriate interventions.

Association Testing of Previously Reported Variants in a Large Case–Control Meta-Analysis of Diabetic Nephropathy

We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10−9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.

Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications.

Objective: Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that counterbalances the actions of angiotensin (AT)II and promotes vasodilatation. Circulating ACE2 activity is increased in diabetes in experimental models. The role of ACE2 in human pathophysiology is unknown. We examined whether ACE2 activity is altered in patients with type 1 diabetes (T1D), with and without diabetic nephropathy. Methods: Quantitative ACE2 activity in serum was measured by a fluorometric assay in 859 patients with T1D in the Finnish Diabetic Nephropathy (FinnDiane) study and in 204 healthy controls. Pulse-wave analysis with augmentation index (AIx) measurement was performed in 319 patients with T1D and 114 controls. Results: ACE2 activity was increased in men with T1D and microalbuminuria (30.2 ± 1.5 ngE/ml) when compared to patients without albuminuria (27.0 ± 0.5 ngE/ml, P < 0.05) or controls (25.6 ± 0.8 ngE/ml, P < 0.05). ACE2 activity was increased in male and female patients who were on ACE inhibitor (ACEi) treatment, also independently of albuminuria. Male and female patients with coronary heart disease (CHD) had significantly increased ACE2 activity (35.5 ± 2.5 vs. 27.0 ± 0.5 ngE/ml, P < 0.001 among male T1D patients vs. male controls). ACE2 activity correlated positively with systolic blood pressure (rs = 0.175, P < 0.001), AIx (rs = 0.191, P = 0.010) and diabetes duration (rs = 0.198, P < 0.001), and negatively with estimated glomerular filtration rate (rs = −0.109, P = 0.016) among male T1D patients. Conclusions: ACE2 activity increases with increasing vascular tone and when the patient with T1D has microvascular or macrovascular disease, indicating that ACE2 may participate as a compensatory mechanism in the regulation of vascular and renal function in patients with T1D.

Physical Activity and Diabetic Complications in Patients With Type 1 Diabetes (The FinnDiane Study).

Physical activity exerts numerous beneficial health effects, and the evidence favoring a physically active lifestyle in the treatment of chronic diseases is substantial (1). For patients with diabetes, physical activity is considered important (2). In theory, regular physical activity may prevent diabetes complications through beneficial effects on glycemic control, insulin sensitivity, blood pressure, lipid profile, and endothelial function. However, physical activity could also cause adverse effects or patients may not be able to exercise due to complications. Little, however, is known about the relationship between physical activity and diabetes complications (3). Therefore, we investigated the associations between physical activity and microvascular and macrovascular diabetic complications in a large cohort of patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study. The FinnDiane Study and the assessment of self-reported leisure-time physical activity (LTPA) by a questionnaire have previously been described (4). This is a cross-sectional analysis of 1,945 patients with data on LTPA. Renal status was based on at least three urine collections. Renal function was evaluated by the Cockcroft-Gault formula (5) for estimated creatinine clearance. Data on retinopathy and cardiovascular disease (CVD) were obtained from medical records. Differences between groups were …

Pulse pressure predicts incident cardiovascular disease but not diabetic nephropathy in patients with type 1 diabetes (The FinnDiane Study).

OBJECTIVE Pulse pressure (PP), an estimate of arterial stiffness, has been shown to be associated with incident cardiovascular disease (CVD) in patients with type 1 diabetes (T1D). However, diabetic kidney disease, a strong predictor of CVD, was not previously taken into account. Furthermore, the role of PP as a predictor of diabetic nephropathy is not known. Therefore, we prospectively investigated the associations between PP and these diabetes complications in patients with T1D. RESEARCH DESIGN AND METHODS A total of 4,509 patients from the FinnDiane Study participated. Follow-up data on incident CVD events and renal status (median 5.3 years) were available in 69 and 76% of the patients, respectively. Altogether, 269 patients (8.6%) had an incident CVD event and 370 patients (10.8%) progressed to a higher level of albuminuria or to end-stage renal disease. RESULTS PP was higher at baseline in patients who experienced a CVD event (66 ± 18 vs. 52 ± 14 mmHg; P < 0.001) or progressed in their renal status (58 ± 18 vs. 54 ± 15 mmHg; P < 0.01) during follow-up. In a Cox regression model, PP was independently associated with a first ever CVD event (hazard ratio per 10 mmHg 1.22 [95% CI 1.10–1.34]) but not progression of renal disease (1.00 [0.89–1.12]) after adjustments for traditional risk factors. CONCLUSIONS PP, a marker of arterial stiffness, is a risk factor for cardiovascular complications but not for diabetic nephropathy in patients with T1D.